Diseases caused by parasites result in severe economic losses in farming industry. Traditional veterinary products used to counter internal parasites were typically formulated for oral application—typically sold as drenches. With a need to improve farming efficiency and minimise labour and animal handling, the trend has been for traditional oral drenches to be replaced by products that are topically applied, typically termed ‘pour-on’ or ‘spot-on’ products. These products are applied to an animal skin area such as the back of the animal usually as a spray, and the compounds in the product act to transfer the active or actives through the skin and into the animal. Formulating such products requires addressing many issues including:                (a) Keeping the actives in a stable liquid form particularly when stored over time often in trying temperature and moisture conditions;        (b) Having a solution viscosity that is easy to use and which can be applied topically via existing equipment;        (c) Ensuring that most if not all of the active or actives pass through the skin layer as intended; and        (d) Ensuring the active or actives used have the desired efficacy.        
Given the varying chemical properties of anthelmintic actives and the relative incompatibility, preparing formulations to achieve the above aims can be challenging, particularly when more than one active is included in a formulation.
Several products are currently available on the market that include macrocyclic lactone anthelmintics for topical application. Many of these use abamectin as the active. Example abamectin based topical products include for example Donaghys ProAbamec™ Pour-On and Baymec™ by Bayer. An alternative is the moxidectin based product sold under the trade name Exodus™ by Merial Ancare.
Several attempts have been made to formulate and commercialise pour-on products that have more than one active ingredient from different chemical classes. The success of these products has been varied and only a small number were successfully commercialised. One example is the product BOSS™ Pour-On for Cattle by Alleva Animal Health Limited, consisting of 1% abamectin and 20% levamisole Base. Another is Combination™ Pour-On for Cattle by Seneca Holdings Limited, consisting of 15% oxfendazole and 10% levamisole Base. Two further examples are Saturn™ Pour-On by Bayer and Eclipse™ Pour-On by Merial Ancare, both consisting of 1% abamectin and 20% levamisole base.
As noted above, formulation challenges exist. The product must remain within specification over the labelled shelf life. In addition macrocyclic lactone and levamisole based products are particularly difficult to formulate together as these two compounds are so chemically incompatible. This incompatibility combined with the higher concentration of levamisole desired for good efficacy renders many common formulation routes unworkable. Other challenges are that the solvent system in pour-on products needs to be non- or low-irritating to the farmer and animal, stable, non-toxic, non-carcinogenic. It is also preferable that a finished product have a viscosity low enough to allow easy dosing yet not so low that the formulation runs off the animal's back or other area to which the formulation is applied. Finally, it is also necessary to achieve full control of parasites and prevent any possible secondary harmful effects, such as causing animal sickness or creating residues in animal meat or milk for human consumption.
Several solvents or combinations of solvents have been described in the art as being suitable for topical transfer of anthelmintic actives.
For example, WO2004/089239 describes a topically applied anthelmintic formulation which comprises at least one macrocyclic lactone and at least one compound selected from praziquantel, morantel and pyrantel. These actives are dissolved in a non-aqueous solvent or solvents mixture that comprises isopropanol, polyethylene glycol, glycerol formal, C8-C10 caprylic/capric triglycerides, diethylene glycol monoethyl ether, propylene glycol monolaureate, dimethylformamide and other compounds.
US2008/0249153 describes an anthelmintic formulation including triclabenzadole in a solution solvent system including at least one solvent selected from 2-pyrrolidone and liquid polyethylene glycol.
WO 2013/043064 discloses a mixture of abamectin and levamisole. However, this mixture degrades rapidly and hence the agents are kept separate (for example, via a two part container) and not mixed until immediately before use.
NZ248486 relates to a stable anthelmintic formulation that comprises a glycol based solvent together with an effective amount of closantel and an effective amount of one or more avermectins or milbemycins. The preferred glycol based solvent contains at least two of water, propylene glycol, polyethylene glycol or glycerol formal.
NZ535644 relates to a pour-on formulation of levamisole base and abamectin, where both actives are dissolved in a solvent system comprising n-methyl-2-pyrrolidone and diethylene glycol n-butyl ether.
NZ336139 describes a veterinary composition comprising at least one ingredient that is lipophilic in character, at least one organic solvent that carries most of lipophilic ingredient, and levamisole dissolved in water.
A similar approach is described in NZ515772 where a macrocyclic lactone, levamisole and benzimidazole are used, where the macrocyclic lactone is dissolved in an organic phase and levamisole and benzimidazole are carried in a pH buffered aqueous system to ensure levamisole stability.
While the above solvents may work, drawbacks exist such as handling issues, potential toxicity issues and the formulations described may lack versatility, for example only being limited to use of levamisole base or salt form and not both forms, or instead only working with one active.
As should be appreciated, while reference has been made above to topically applied formulations, similar formulation issues may exist for delivery via other routes e.g. oral or parenteral routes of administration, and the discussion regarding topical administration above should not be seen as limiting. Further, whilst some products exist, formulations including multiple anthelmintic actives that offer alterative solvent systems may provide alternate advantages or at least may provide the public with a choice.
Further aspects of the formulations, methods and use will become apparent from the ensuing description that is given by way of example only.